Covalent Arabinoxylans Nanoparticles Enable Oral Insulin Delivery and Gut Microbiota Modulation in Diabetes

Arabinoxylans (AX) are polysaccharides capable of forming covalent gels stable under variations in pH and temperature. They are fermentable by the colonic microbiota, making them appropriate carriers for colon-targeted oral drug delivery, including insulin. This study aimed to fabricate covalent AX nanoparticles loaded with insulin (NPAXI) using a 0.25 (AX/insulin) mass ratio and to evaluate their colon-targeted capacity to improve glycemic control in diabetic rats. In parallel, we assessed gut microbiota modulation as a secondary outcome, derived from the prebiotic fermentation of AX, considered an additional benefit. NPAXI, produced by coaxial electro spraying, displayed a mean diameter of 661 nm, a zeta potential of −31 mV, and high insulin encapsulation efficiency. Bioassay demonstrated that a single oral NPAXI dose restored normoglycemia for 9 h, starting 15 h post-administration. Gut microbiota analysis revealed that while insulin alone increased Lactobacillaceae, it failed to suppress Enterobacteriaceae. NPAXI treatment, however, promoted beneficial taxa such as Muribaculaceae and Prevotellaceae and reduced proinflammatory families like Desulfovibrionaceae and Helicobacteraceae. These microbial shifts paralleled the improved glycemic profile, suggesting a synergistic interaction between AX and insulin in reestablishing gut microbial homeostasis and metabolic regulation. Overall, NPAXI represents a promising strategy for colon-targeted oral insulin delivery, offering additional microbiota-modulating benefits.